The PERK pathway of the unfolded protein response (UPR) is emerging as a therapeutic target in diseases of protein homeostasis (proteostasis), including diseases of myelin like multiple sclerosis, leukodystrophies and Charcot Marie Tooth (CMT) neuropathies. We showed that downstream effectors of PERK such as Gadd34 are valid therapeutic targets in CMT1B-S63del mice. These studies suggested that inhibiting Gadd34 resets proteostasis towards translational attenuation and this is beneficial in S63del nerves. However, rescue of myelination in these pilot experiments was incomplete, suggesting that PERK may modulate myelination in additional ways. Indeed, we made the surprising observation that ablating PERK from Schwann cells actually improved myelination. This suggests that activated PERK aggravates pathology in S63del nerves. Therefore, this effect of PERK may include targets outside of the canonical UPR. We hypothesize that PERK interferes with myelination both by perturbing proteostasis within the UPR, and also by interfering with pro- myelinating mediators outside of the UPR. In this proposal, we will use PERK ablation in S63del nerves to identify the various ways in which the PERK pathway may influence myelination. Thus, we will identify new PERK-interacting proteins and substrates. We will also determine whether PERK interferes with Calcineurin A, a pro-myelinating mediator of neuregulin signaling. Finally, we will perform a preclinical trial in S63del mice of Sephin1, a novel Gadd34 inhibitor that limits reactivation of translation during ER stress. The results of these studies will identif therapeutic PERK targets not only within the UPR, but will also motivate a search for how PERK affects other cell or tissue-specific functions outside of the UPR, and provide new therapeutic targets for 10 or more CMT neuropathies, and other diseases of proteostasis.